Purification of HMG-CoA synthase and HMG-CoA lyase will permit detailed study of the catalytic mechanisms of these enzymes and also as investigation of how interaction of certain mitochondrial metabolites with these enzymes may alter HMG-CoA cycle activity. Study of the properties of HMG-CoA cycle enzymes will facilitate the design of experiments which will unambiguously and quantitatively determine changes in enzyme activity which occur upon transition from the normal to the ketotic state. Enzymes which display a change in activity that explains the elevated ketogenic capacity characteristic of the diabetic state will be studied in detail. The question of whether enzyme activation is due to an increase in the number of enzyme molecules (long-term control) or due to modification of pre-existing enzyme (short term control) will be addressed.